DESCRIPTION (adapted from applicant's abstract): Abnormalities of human cortical development are a major cause of mental retardation and epilepsy. Lamination of the neocortex depends on crucial early steps, including migration of the earliest cortical plate (CP) neurons that split the preplate and form the marginal zone (MZ) and subplate (SP). Neurotrophin-4 (NT4) causes a large excess of neurons to migrate into the embryonic cortical MZ, in vivo and in vitro, forming heterotopias that distort the underlying CP. These excess neurons share the birthdate and phenotype of subpial granular layer (SGL) neurons of the MZ. Post-natally, animals exposed in utero to NT4 have a second type of CP heterotopia that appears to be caused by the abnormally abundant processes of MZ neurons; these animals have recurrent seizures and die. The goals of this proposal are i) determine the mechanisms that distinguish early and late CP Formation; ii) determine the role of NT4 during normal MZ development, and iii) determine how the T4-induced CP heterotopias form. The specific aims are 1) Determine the mechanisms of radial migration in neocortex: Test the hypotheses that a) neurons destined to split the preplate and form the earliest CP (layer 6), l translocate their cell bodies in a non-glial-guided mechanism that is reelin-dependent, but cdk5/ II 35 independent, and b) neurons, destined for layers 5 and above, migrate via glial-guided mechanisms that are both reelin and cdkS/p35 dependent. 2) Test the hypothesis that the number and phenotype of SGL neurons in the MZ are regulated by NT4 and TrkB. 3) Test the hypothesis that NT4 induces SGL neurons to migrate into the MZ from the retrobulbar "waiting area" and developing striatum 4) Determine the evolution of postnatal CP heterotopias by testing the hypothesis that NT4-induced CP heterotopias form because large groups of cortical neurons are surrounded by aberrantly positioned MZ neurons and their extensive processes. These results suggest that excess production of (or hypersensitivity to) NT4 during early cortical development may play a role in the pathogenesis of human FCDs, and that certain FCDs may arise as a primary disturbance in the development of MZ neurons, secondarily affecting the architecture of subsequent cortical layers. This model should be a valuable tool for identifying the mechanisms underlying the epileptogenicity of dysplastic cortex.